high frequency oscillation and tracheal gas insufflation in patients with severe acute respiratory distress syndrome and traumatic brain injury an interventional physiological study

R E S E A R C H Open AccessHigh-frequency oscillation and tracheal gas insufflation in patients with severe acute respiratory distress syndrome and traumatic brain injury: an interventio

R E S E A R C H Open Access

High-frequency oscillation and tracheal gas

insufflation in patients with severe acute

respiratory distress syndrome and traumatic brain injury: an interventional physiological study

Charikleia S Vrettou, Spyros G Zakynthinos, Sotirios Malachias and Spyros D Mentzelopoulos*

Abstract

Introduction: In acute respiratory distress syndrome (ARDS), combined high-frequency oscillation (HFO) and

tracheal gas insufflation (TGI) improves gas exchange compared with conventional mechanical ventilation (CMV)

We evaluated the effect of HFO-TGI on PaO2/fractional inspired O2 (FiO2) and PaCO2, systemic hemodynamics, intracranial pressure (ICP), and cerebral perfusion pressure (CPP) in patients with traumatic brain injury (TBI) and concurrent severe ARDS

Methods: We studied 13 TBI/ARDS patients requiring anesthesia, hyperosmolar therapy, and ventilation with

moderate-to-high CMV-tidal volumes for ICP control Patients had PaO2/FiO2 <100 mm Hg at end-expiratory

pressure≥10 cm H2O Patients received consecutive, daily, 12-hour rescue sessions of HFO-TGI interspersed with 12-hour periods of CMV HFO-TGI was discontinued when the post-HFO-TGI PaO2/FiO2 exceeded 100 mm Hg for

>12 hours Arterial/central-venous blood gases, hemodynamics, and ICP were recorded before, during (every 4 hours), and after HFO-TGI, and were analyzed by using repeated measures analysis of variance Respiratory

mechanics were assessed before and after HFO-TGI

Results: Each patient received three to four HFO-TGI sessions (total sessions, n = 43) Pre-HFO-TGI PaO2/FiO2(mean

± standard deviation (SD): 83.2 ± 15.5 mm Hg) increased on average by approximately 130% to163% during HFO-TGI (P < 0.01) and remained improved by approximately 73% after HFO-HFO-TGI (P < 0.01) Pre-HFO-HFO-TGI CMV plateau pressure (30.4 ± 4.5 cm H2O) and respiratory compliance (37.8 ± 9.2 ml/cm H2O), respectively, improved on

average by approximately 7.5% and 20% after HFO-TGI (P < 0.01 for both) During HFO-TGI, systemic

hemodynamics remained unchanged Transient improvements were observed after 4 hours of HFO-TGI versus pre-HFO-TGI CMV in PaCO2 (37.7 ± 9.9 versus 41.2 ± 10.8 mm Hg; P < 0.01), ICP (17.2 ± 5.4 versus 19.7 ± 5.9 mm Hg; P

< 0.05), and CPP (77.2 ± 14.6 versus 71.9 ± 14.8 mm Hg; P < 0.05)

Conclusions: In TBI/ARDS patients, HFO-TGI may improve oxygenation and respiratory mechanics, without

adversely affecting PaCO2, hemodynamics, or ICP These findings support the use of HFO-TGI as a rescue

ventilatory strategy in patients with severe TBI and imminent oxygenation failure due to severe ARDS

Introduction

The management of patients with traumatic brain injury

(TBI) becomes challenging when complicated by acute

respiratory distress syndrome (ARDS) [1,2] Hypoxemia,

hypercapnia, and hypotension are rather frequent in ARDS, either as original clinical manifestations, or as con-sequence(s) of the conventional mechanical ventilation (CMV) strategy [3-5] TBI ventilatory goals include ade-quate oxygenation as well as CO2elimination for the con-trol of intracranial pressure (ICP) and cerebral perfusion

* Correspondence: sdm@hol.gr

First Department of Intensive Care Medicine, National and Kapodistrian

University of Athens Medical School, Evaggelismos General Hospital, Athens,

Greece

© 2013 Vrettou et al.; licensee BioMed Central Ltd This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in

pressure (CPP) [5,6] However, the use of

moderate-to-high tidal volumes and moderate-to-high respiratory rates predisposes

TBI patients to ventilator-induced lung injury [4,5]

High-frequency oscillation (HFO) aims at optimizing

lung protection [7-10] and recruitment [11] However,

data on the effects of HFO on PaCO2, hemodynamics,

and ICP in patients with TBI and ARDS are sparse and

originate from small, retrospective case series [12-14]

Increases in ICP secondary to transient increases in

PaCO2 have previously been reported during HFO

[12,13] Hypercapnia occurs commonly during HFO,

even at relatively low HFO frequencies of ~5 Hz [15]

Conversely, the addition of tracheal gas insufflation

(TGI) to HFO enhances CO2 elimination [16,18], and

improves oxygenation [16-19] In the present study, we

hypothesized that rescue sessions of HFO-TGI

adminis-tered to TBI patients with severe ARDS could result in

improved gas exchange, higher post-HFO-TGI

respira-tory compliance, and less-traumatic CMV pressures

[19], without adversely affecting ICP and/or CPP

Materials and methods

The study was conducted between June 2009 and June

2012 in the mixed medical and surgical 30-bed intensive

care unit (ICU) of Evaggelismos Hospital, Athens, Greece

Informed, written next-of-kin consent was obtained for all

participants The study was approved by the Scientific

Council and the Ethics Committee of Evaggelismos

Hospital

Patients

Eligible patients had early (that is, onset within≤72 hours)

ARDS [19,20] with severe oxygenation disturbances

(defined as PaO2/fractional inspired O2(FiO2)≤ 100 mm

Hg at positive end-expiratory pressure (PEEP)≥10 cm

H2O), and severe TBI (that is, preintubation Glasgow

Coma Score <8 [21]) Target ICP was≤20 mm Hg; thus,

the threshold for increasing therapy-intensity level (TIL)

for ICP control was ICP > 20 mm Hg [5,6,22] TIL

comprised a minimum of head elevation (20 degrees to

30 degrees relative to horizontal), higher-dose sedation/

neuromuscular blockade, hemodynamic support to

main-tain a target CPP of≥60 mm Hg [5,6,22], hyperosmolar

therapy, and prevention of hyperthermia ([23]; see also

Additional file 1)

We applied previously published exclusion criteria ([19];

Additional file 1), in addition to ICP >30 mm Hg, and

brain death or imminent risk of brain herniation Patient

monitoring included continuous display of

electrocardio-graphic lead II and peripheral oxygen saturation,

intraar-terial blood pressure, cardiac output/index (PICCO-plus;

Pulsion Medical Systems, Munich, Germany), core patient

temperature, and ICP (Codman ICP monitoring system;

Codman & Shurtleff, Raynham, MA, USA)

Study design

We conducted a prospective, interventional, noncontrolled study on the physiological effects of intermittent, rescue HFO-TGI in TBI/ARDS patients In a recent randomized controlled trial of severe ARDS [19], we showed that 6 or more-hour HFO-TGI sessions (average daily HFO-TGI use, 12.4 hours) with recruitment maneuvers (RMs) are associated with significant improvements in oxygenation, plateau pressure, and respiratory compliance during post-session CMV versus prepost-session CMV; HFO-TGI did not significantly affect hemodynamics Our rescue intervention comprised daily, 12-hour sessions of HFO-TGI and RMs, interspersed with 12-hour periods of CMV (Figure 1) The rescue intervention was discontinued when a PaO2/FiO2

of >100 mm Hg could be maintained for >12 hours during post-HFO-TGI CMV, with CMV-plateau airway pressure

of≤35 cm H2O

Study protocol Baseline CMV period

Details are provided in Additional file 1 On enrolment, patients were ventilated with attending physician-prescribed volume assist-control CMV CMV settings were already titrated to the best possible combinations of PaO2/FiO2(target ≥100 mm Hg, with PaO2maintained

>90 mm Hg [5,22]), PaCO2 (target 35 to 45 mm Hg), plateau pressure (target,≤35 cm H2O), and ICP/CPP An arterial blood gas analysis was performed, respiratory mechanics were assessed with rapid end-inspiratory/end-expiratory airway occlusion [16-19], and the Murray score [24] was calculated

Tracheal tube (inner diameter, 8.0 to 9.0 mm) correct positioning and patency were verified, and a circuit adapter/TGI-catheter system was inserted, as previously described [16-19]; Additional file 1 Sixty minutes there-after, we conducted the study’s baseline, physiologic CMV measurements (arterial/central venous blood gas analysis, hemodynamics and ICP, and respiratory mechanics) at FiO2= 1.0 (Figure 1)

HFO-TGI and RMs protocol

Patients were connected to the 3100B HFO ventilator (Sensormedics; Yorba Linda, CA, USA), and after a

10-to 20-second period of standard HFO ventilation, a 20-second RM was performed by pressurizing the HFO breathing circuit at 40 to 45 cm H2O with the oscillator piston off RMs were administered only to patients with ICP≤25 mm Hg and CPP ≥60 mm Hg during pre-HFO-TGI CMV RM-abort criteria were ICP increase to >25

mm Hg or CPP decrease to <60 mm Hg during an RM; whenever these criteria were met, RMs were suspended until the HFO-TGI session of the next study day

Initial HFO settings (Figure 1) were aimed at optimizing lung recruitment and PaCO2control A tracheal tube cuff leak and TGI were used as previously described (Figure 1

[16-19]; Additional file 1) For study purposes, we

docu-mented physiological measurements (arterial/central

venous blood gas analysis, and hemodynamics/ICP) at 4,

8, and 12 hours after HFO initiation The sequence of

RMs, oxygenation-based titrations in mean airway

pres-sure (mPaw), and PaCO2-based titrations of HFO

fre-quency and oscillatory pressure amplitude (ΔP) is

illustrated in Figure 1 If, at 12 hours, the PaO2/FiO2was

still <100 mm Hg, the daily HFO-TGI session was to be

extended for at least 24 hours (that is, until the end of the

next day’s session [19])

In the event that ICP would exceed the pre-HFO-TGI

value by 5 mm Hg, or reach 30 mm Hg in absolute value

for >15 minutes, the HFO-TGI session was to be

inter-rupted, with consequent return to pre-HFO-TGI CMV

and cancellation of any further HFO-TGI intervention

During HFO-TGI, any RM-and/or HFO-TGI-associated hypotension (defined as mean arterial pressure <70 mm Hg) lasting for >1 minute was to be treated with norepi-nephrine and/or a 300 to 500-ml bolus of crystalloid [19]

Post HFO-TGI CMV period

If, after 12 hours of HFO-TGI, PaO2/FiO2exceeded 100

mm Hg, patients were returned to CMV with the pre-HFO-TGI settings (including the FiO2= 1.0) maintained unchanged for 30 minutes Subsequently, we performed the post-HFO-TGI physiological measurements Further-more, within the next 12 hours, CMV ventilatory settings and TIL for ICP control were retitrated as necessary, in concordance with the previously described targets and limits Twelve hours after return to CMV, patients were assessed for return to HFO-TGI, according to the pre-viously described, oxygenation/plateau-pressure criterion

Figure 1 Schematic representation of the study protocol CMV, conventional mechanical ventilation; RM, recruitment maneuver; HFO, high-frequency oscillation; TGI, tracheal gas insufflation; mP aw , mean airway pressure; f, oscillation frequency; ΔP, oscillatory pressure amplitude; minV, minute ventilation; FiO 2 , fractional inspired oxygen *Includes the (1) confirmation of correct positioning and patency of tracheal tubes by chest radiography and 10-second or less fiberoptic endoscopy, respectively [19-21,23]; (2) introduction of a TGI catheter (through a dedicated circuit adapter) and positioning of the TGI catheter tip at 0.5 to 1.0 cm beyond the tracheal tube tip, as previously described [[18-20,22]; Additional file 1]; and (3) minor ventilatory adjustments aimed at further, concurrent optimization of PaCO 2 , intracranial pressure, and plateau pressure

(Additional file 1) This patient preparation was carried out once, immediately after study enrolment †Period duration was as illustrated on study day 1; on a subsequent study day, it constituted a 60-minute pre-HFO-TGI CMV period that followed the 11-hour post-HFO-TGI CMV period of the preceding study day §Depending on tracheal tube inner diameter (9.0, 8.5, or 8.0 mm) [17], the HFO mP aw was set at 10, 12, or 15 cm H 2 O (respectively) above preceding CMV mP aw [20] ‡Performed by pressurizing the HFO breathing circuit at 40 to 45 cm H 2 O for 20 seconds with oscillator piston off **Causing a 3- to 5-cm H 2 O decrease in mP aw , which was reversed by adjusting the mP aw valve; the tracheal tube cuff leak was placed immediately after the first RM #PaCO 2 of HFO-TGI was to be maintained within 30 to 50 mm Hg.

The last 60 minutes of this CMV period corresponded to

the pre-HFO-TGI CMV period of the subsequent study

day (Figure 1) We conducted all daily, pre-HFO-TGI,

physiological, CMV measurements with CMV FiO2set at

1.0 for≥15 minutes

Data collection and statistical analysis

On each study day, we obtained physiological

measure-ments over 5-minute periods at the previously mentioned

five times (Figure 1) For each 5-minute period,

continu-ously monitored variables were recorded once per minute

and then averaged Standard formula-derived variables

included shunt fraction, peripheral O2delivery rate, CPP,

respiratory compliance, and oxygenation index (Additional

file 1) Daily physiological data sets from each patient were

pooled and analyzed

We conducted a compromise power analysis (G*Power

version 3.1; Duesseldorf University, Duesseldorf, Germany),

For a small effect sizef of 0.10, a beta-to-alpha ratio of 4:1,

a total of 40 daily data sets (that is, observations), five levels

of the within-subjects factor (that is, ventilatory technique),

and a nonsphericity correction of 0.3 [17], the analysis

yielded an alpha value of 0.044, and a power of 0.83 We

estimated that each patient would require three or more

HFO-TGI sessions [19], each corresponding to one

study-data set [17] Consequently, a minimum of 13 patients

would be required for study completion

Data were analyzed by using SPSS Statistics version 20

(SPSS Inc., Chicago, IL, USA) and reported as mean ±

standard deviation (SD) Distribution normality was tested

by using the Kolmogorov-Smirnov test Physiological

vari-able data obtained at the reported measurement time

points were compared with repeated measures analysis of

variance for one within-subjects factor The Bonferroni

correction was used for pairwisepost hoc comparisons

Pre-HFO-TGI and post-HFO-TGI CMV plateau pressure

and respiratory-compliance data were compared with a

pairedt test Significance was set at P < 0.05

Results

During the study period, we administered rescue

HFO-TGI sessions to 13 eligible TBI/ARDS patients Table 1

displays baseline data of the patients, their Marshall score

[25] on hospital admission and their neurologic outcome

On enrolment, six patients had ICP >20 mm Hg and/or

CPP <60 mm Hg; average, total TIL score was 17.3 ± 5.1

(range, 11 to 28; Additional file 1, Table S1 [23]) Nine

and four patients required a total of three and four daily

HFO-TGI sessions (respectively), according to our

prespe-cified oxygenation criteria No need was seen for extension

or interruption of any HFO-TGI session, and none of the

HFO-TGI sessions was cancelled In 13 (30.2%) of 43

HFO-TGI sessions, RMs were cancelled (n = 11) or

aborted (n = 2) (see Additional file 1, Table S2)

Secondary insults, such as ICP >20 mm Hg, and CPP

<60 mm Hg with/without concurrent hypotension, were recorded in 23 (53.5%) of 43 study days corresponding to nine (69.2%) of 13 patients Insults were effectively treated with further increases in TIL In all of these cases, at least one insult occurred during CMV Insults during HFO-TGI were recorded in 19 (44.2%) of 43 study days and in seven (53.8%) of 13 patients (full relevant data reported in Addi-tional file 1, Table S2) This is consistent with the subse-quently reported improvements in ICP and CPP control observed during HFO-TGI In three (7.0%) of 43 study days, concurrent increases in post-HFO-TGI PaCO2(of

>5 mm Hg) and ICP (to 23 to 26 mm Hg) were treated mainly by increasing CMV minute ventilation by 1 to

2 L/min (Additional file 1, Supplement to Results and Table S2)

We did not observe any of the potential HFO and/or TGI-associated complications [16-19], apart from transi-ent hypotension within the first 2 minutes of HFO-TGI initiation This protocol-related complication occurred just after the 20-second first RM in nine (20.9%) of

43 HFO-TGI sessions, corresponding to six (46.2%) of

13 patients In all cases, the pre-HFO-TGI hemodynamic status was restored within 15 minutes after a temporary increase in vasopressor infusion and a fluid bolus (see Methods and Additional file 1, Supplement to Results and Figure S1)

Ventilatory parameters and results on physiological variables

We used CMV tidal volume, respiratory rate, minute ven-tilation, and PEEP of 8.3 ± 1.3 ml/kg predicted body weight, 26.6 ± 5.0 breaths/min, 15.0 ± 2.9 L/min, and 14.6

± 2.6 cm H2O, respectively Table 2 displays the HFO-TGI settings (along with CMV mPaw; see also Figure 1), results

on oxygenation index, and CMV respiratory mechanics HFO-TGI resulted in significant improvements in plateau pressure and respiratory compliance (P < 0.01)

Results on PaO2/FiO2, PaCO2, pH, and cerebral hemo-dynamics are shown in Figure 2 PaO2/FiO2was higher during HFO-TGI sessions versus pre-/post-HFO-TGI CMV (P < 0.01) Furthermore, PaO2/FiO2remained higher during post-HFO-TGI CMV versus pre-HFO-TGI CMV (P < 0.01) Accordingly, HFO-TGI was associated with sig-nificant improvements in oxygenation index (Table 2), shunt fraction, central-venous O2saturation, and periph-eral O2delivery (Table 3) Furthermore, PaCO2and pH were improved after 4 hours of HFO-TGI relative to pre/ post HFO-TGI CMV, and after 8 hours of HFO-TGI rela-tive to post-HFO-TGI CMV (Figure 2) ICP and CPP were also improved after 4 hours of HFO-TGI relative to pre/ post HFO-TGI CMV (Figure 2) Last, besides the RM-associated hypotension, HFO-TGI did not affect systemic hemodynamics (Table 3)

Table 1 Patient baseline characteristics, ventilatory settings on study enrollment, and outcome

TBI etiology

Road traffic accident, no/total no (%) 12/13 (92.3)

Fall from height >5 meters, no/total no (%) 1/13 (7.7)

Marshall classification of brain CT findings on hospital admission

Grade III: Diffuse injury and swelling, no./total no (%) 7/13 (53.9)

Grade VI: Nonevacuated mass lesion >25 ml, no/total no (%)c, d 6/13 (46.2)

Simplified Acute Physiology Score IIe 48.2 ± 11.9

Thiopental infusion, no/total no (%)f, g 4/13 (30.1)

PaO 2 /inspired O 2 fraction (mm Hg)f 85.9 ± 12.2

Positive end-expiratory pressure (cm H 2 O) f 13.9 ± 2.9

End-inspiratory plateau airway pressure (cm H 2 O) f 33.5 ± 4.7

Quasistatic respiratory compliance (ml/cm H 2 O)f, i 31.5 ± 6.1

Outcome according to GOSE

Upper good recovery (GOSE = 8), no/total no (%)m 5/13 (38.5)

Lower good recovery (GOSE = 7), no/total no (%) m 2/13 (15.4)

Values are mean ± SD unless otherwise specified TBI, traumatic brain injury; CT, computed tomography; PBW, predicted body weight; ARDS, acute respiratory distress syndrome; GOSE, Glasgow Outcome Scale Extended.

a

For males, PBW was calculated as 50 + (height (cm) - 152.4) × 0.91; for females, 45.5 + (height(cm) - 152.4) × 0.91.

b

Refers to the time interval between TBI and study enrollment.

c

Two patients with epidural hematoma and two patients with subdural hematoma were treated with neurosurgical evacuation within the first 3 hours after hospital admission; on follow-up CT, three patients had diffuse injury III, and one patient (also subjected to decompressive craniectomy) had diffuse injury IV findings.

d

Two patients with intracerebral hemorrhage received a ventriculostomy; on follow-up CT, one patient had diffuse injury III, and one patient had diffuse injury II findings.

e

Determined within 12 hours before study enrolment.

f

Recorded/determined within 10 minutes after study enrolment.

g

In all four patients, a thiopental infusion of 6 mg/kg/h was started within 24 hours before study enrolment, because their intracranial pressure exceeded 30 mm

Hg, despite the preceding combined use of propofol/midazolam anesthesia, hyperosmolar therapy, and increased minute ventilation.

h

Calculated as mean airway pressure divided by the PaO2/inspired O2 fraction, and then multiplied by 100.

i

Calculated as tidal volume divided by the difference between the end-inspiratory and end-expiratory plateau airway pressures.

k

Refers to the time interval between establishment of ARDS diagnosis and study enrolment.

l

Eleven patients had severe, bilateral ventilator-associated pneumonia caused by Klebsiella pneumoniae (n = 5), or Acinetobacter baumannii (n = 4), or

Pseudomonas aeruginosa (n = 2) Four patients had bilateral pulmonary contusions, and one of them also had a new, unilateral area of consolidation with air-bronchogram, also attributed to ventilator-associated pneumonia with Acinetobacter baumannii One patient also received a massive blood transfusion within the first 48 hours after hospital admission.

m

Determined at approximately 3 months after hospital discharge; data originate from patient follow-up records of the University-affiliated Department of Neurosurgery of Evaggelismos Hospital.

n

Corresponds to death in the intensive care unit within 6 to 16 days after study enrolment (see also Table S2 in Additional file 1).

Our results support the use of HFO-TGI as rescue

ventil-atory strategy in patients with severe TBI and imminent

oxygenation failure due to severe ARDS In TBI, even

a mild arterial hypoxemia (for example, PaO2 = 55 to

58 mm Hg) can cause cerebral vasodilation and

exacerba-tion of intracranial hypertension [5,26] The linear relaexacerba-tion

between PaCO2and cerebral blood flow and volume [27]

mandates control of PaCO2as well

Current and prior [16-19] results indicate that HFO-TGI

substantially improves oxygenation versus CMV Relative

to both CMV and standard HFO, HFO-TGI augments

lung base recruitment [16,18] The high-velocity TGI jet

stream likely enhances HFO-dependent gas-transport

mechanisms, such as the asymmetry in inspiratory velocity

profiles, radial gas mixing, and molecular diffusion [16,17]

TGI also augments dead-space clearance and HFO tidal

volume and alveolar ventilation, thereby improving CO2

elimination [16,18]

During our current HFO-TGI technique, we used a

tra-cheal tube cuff leak, a high bias flow, and frequency and

ΔP settings that correspond to an HFO tidal volume of

180 to 200 ml (Figure 1; Table 2[28]) The latter

constitu-tes a 65% to 67% reduction of the pre-HFO-TGI CMV

tidal volume and is consistent with improved lung

protec-tion [10] A better lung protecprotec-tion during post-HFO-TGI

CMV relative to pre-HFO-TGI CMV is also suggested by

our favorable results on post-HFO-TGI respiratory

mechanics (Table 2; [19])

Assuming a stable chest-wall elastance (Ecw) during the

daily time intervals of the study protocol (Figure 1), the

observed increase in respiratory compliance (that is,

decrease in respiratory elastance) should reflect a decrease

in lung elastance (EL) due to HFO-TGI-associated

recruit-ment [16-19] Also, intrapleural pressure (Ppl) is given by

the equation

Ppl = airway pressure× Ecw



(EL+ Ecw)

This means that for the same airway pressure level and

Ecw, a decrease in ELis associated with an increase in Ppl Furthermore, in the present study, the average ventilator-displayed HFO mPaw during HFO-TGI exceeded the preceding average CMV mPaw by about 11 cm H2O (Table 2) Consequently, Pplwas probably increased dur-ing HFO-TGI compared with CMV

An increase in Pplcould impede systemic and jugular venous return, decrease cardiac output/index and mean arterial pressure, increase ICP, and decrease CPP [30]

In contrast, we observed an initial improvement in cere-bral hemodynamics during HFO-TGI (Figure 2) Possible explanatory factors include (a) the mPawdecrease along the tracheal tube during HFO-TGI, which results in a mean tracheal pressure that is 5 to 6 cm H2O lower than the ventilator-displayed HFO mPaw[16,19]; this means that the present study’s actual, HFO-TGI-induced increase

in average mean tracheal pressure was probably within 5

to 7 cm H2O [16]; and (b) an HFO-TGI-induced lung recruitment without concurrent hyperinflation [18]; this is consistent with our favorable results on oxygenation/shunt fraction, and PaCO2(Figure 2 and Table 3)

A prior study of TBI/ARDS [31], showed that ICP and CPP remain stable when an increase in ventilation pres-sures (through PEEP increase from 0 to 10 cm H2O) augments lung recruitment, without affecting PaCO2 Alternative, rescue ventilatory strategies for severe TBI/ARDS patients include prone positioning [5], high-frequency percussive ventilation (HFPV) [5], CMV-TGI [32], pumpless extracorporeal lung assist (pECLA) with

a heparin-coated circuit [5,33], and extracorporeal mem-brane oxygenation (ECMO) [34] Regarding the use of the first two strategies in TBI/ARDS, only scarce and inconclusive published data exist [5] CMV-TGI may allow less-traumatic CMV settings while maintaining PaCO2 control [32] CMV-TGI has the limitations of TGI [35], without the option of cuff leak use to lower expiratory airway resistance pECLA and ECMO may result in better gas exchange and lung protection, with

Table 2 Ventilatory parameters of HFO-TGI sessions, oxygenation index, and respiratory mechanics

Ventilatory technique mP aw (cm H 2 O) Frequency

(Hz) ΔP (cm H 2 O) TGI flow

(L/min)

Oxygenation Index

Pplateau (cm H 2 O)

Cst (ml/cm H 2 O) Pre HFO-TGI CMV 20.5 ± 3.1 NA NA NA 26.0 ± 8.5 30.4 ± 4.5 37.8 ± 9.2 HFO-TGI (4 hours) 31.6 ± 3.9 3.5 ± 0.4 80.9 ± 7.3 3.5 ± 0.4 20.6 ± 10.5* NA NA

HFO-TGI (8 hours) 30.9 ± 4.3 3.6 ± 0.6 80.4 ± 8.5 3.6 ± 0.8 17.5 ± 7.8* NA NA

HFO-TGI (12 hours) 30.2 ± 5.0 3.7 ± 0.9 80.1 ± 8.6 3.7 ± 0.9 15.3 ± 5.9*,§ NA NA

Post HFO-TGI CMV 19.5 ± 3.0 NA NA NA 15.3 ± 5.9* ,§ 28.2 ± 4.6* 45.3 ± 13.1* Values are mean ± SD CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI tracheal gas insufflation; pre-HFO-TGI CMV, corresponds to either the baseline CMV period of study day 1 or the 60-minute period that followed the 11-hour period of post-HFO-TGI CMV of the preceding study day (see also Figure 1 and corresponding legend); mPaw, mean airway pressure, ΔP, oscillatory pressure amplitude; Pplateau, end-inspiratory plateau airway pressure; Cst, static respiratory system compliance; NA, not applicable.

*P < 0.01 versus pre-HFO-TGI CMV.

§

P < 0.01 versus HFO-TGI at 4 hours.

minimal concurrent risk of anticoagulation-induced side

effects [5,33,34]

Methodologic considerations

While designing the study, we anticipated that in severe

TBI patients, any new, ARDS-associated hypoxemia and/

or hypercapnia could cause reversible ICP perturbations

to values >20 mm Hg [5,22] Furthermore, we considered

that an ICP level of 30 mm Hg constitutes an upper limit

for its eventual and effective control to≤20 mm Hg

through increases in TIL [36] Thus, we chose this

particular upper ICP limit for both study enrolment and completion of our HFO-TGI intervention Accordingly, regarding RMs, we chose an upper limit of ICP = 25 mm

Hg, because we expected that any potential ICP increase associated with a 20-second RM would most likely be≤5

mm Hg, thus resulting in a maximal ICP of≤30 mm Hg during post-RM HFO-TGI [19] This prediction is con-sistent with the results of a prior study, which also used ICP >25 mm Hg as the RM-abort criterion [35]

During pressure-controlled CMV, a 60-second RM with an incremental peak pressure of up to 60 cm HO

Figure 2 Results on gas-exchange and cerebral hemodynamics CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation; pre-HFO-TGI CMV corresponds to either the baseline CMV period of study day 1, or the 60-minute period that followed the 11-hour period of post-HFO-TGI CMV of the preceding study day (see also Figure 1 and corresponding legend) Left: results on PaO 2 /fractional inspired oxygen (FiO 2 ) (top diagram), PaCO 2 (middle diagram), and arterial pH (bottom diagram) obtained, during CMV1 (that is, just before HFO-TGI initiation), HFO-TGI at 4, 8, and 12 hours, and CMV2 (that is, at 30 minutes after HFO-TGI discontinuation; see also Figure 1 and corresponding legend) Right: results on intracranial pressure (top diagram) and cerebral perfusion pressure (bottom diagram) also obtained

at the previously mentioned time points Squares and error bars represent mean and SD, respectively *P < 0.01 versus pre-HFO-TGI CMV †P < 0.01 versus post-HFO-TGI CMV §P < 0.05 versus pre-HFO-TGI CMV and post-HFO-TGI CMV ‡P < 0.05 versus pre-HFO-TGI CMV.

(pressure level sustained for 30 seconds) may decrease

mean arterial pressure by about 15% and increase ICP

by about ~23%, with concurrent reductions of about

17% in CPP [35] We applied a continuous positive

air-way pressure of 40 to 45 cm H2O for just 20 seconds

In nine HFO-TGI sessions, the first RMs were

asso-ciated with average decreases of about 35% and about

44% in mean arterial pressure and CPP (respectively)

versus pre-HFO-TGI CMV; furthermore, within 1 to 2

minutes after RM, the ICP increased by about 19%

ver-sus pre-HFO-TGI CMV (see Additional file 1, Figure

S1) These protocol-related, secondary insults were

promptly reversed by a temporary increase in

vasopres-sor support and volume loading Insults did not recur

after subsequent RMs within the same HFO-TGI

ses-sion, and occurred independent of session order

(Addi-tional file 1, Supplement to Results, and Figure S1)

Volume-status optimization may have prevented

transi-ent hypotension after the second and third RM of the

HFO-TGI sessions [37]

Study limitations

Limitations of long-term TGI include the impact of the

high-velocity jet stream and/or an oscillating TGI

cathe-ter on the tracheal wall, causing mucosal necrosis and/

or hemorrhage [16-19,38,39], the inspissation of

secre-tions with the potential for partial or complete airway

obstruction in case of inadequate humidification of TGI

gas [16-19,38,40], and dynamic pulmonary

hyperinfla-tion, hemodynamic compromise, and pneumothorax

caused by the forward-thrust TGI that can impede

expiration [16-19,38] Other potential complications

include venous gas embolism, interference of a TGI

catheter passed through the tracheal tube with suction-ing [38], TGI catheter obstruction by secretions [19], and absence of commercially available equipment speci-fically designed for TGI administration [16-19,38] In our clinical practice, we intermittently superimpose humidified TGI gas to HFO, and most frequently, for

≤12 hours [19] Furthermore, during HFO-TGI, we use

a tracheal tube cuff leak, to increase the effective width

of the expiratory pathway, and thus reduce the risk of hyperinflation and promote CO2elimination [8,16-19]

In the present study, the use of brain-tissue O2 moni-toring could have clarified the relation between the HFO-TGI-induced improvement in arterial oxygenation and the oxygenation of the brain tissue It would have also have been of great interest to include transcranial Doppler ultrasonography measurements as part of the trial, to investigate the effect of HFO-TGI on cerebral blood flow Finally, the study was noncontrolled and nonrandomized However, it provides the first support-ing data on the feasibility, efficacy, and safety of HFO-TGI in severe TBI/ARDS

Conclusions

HFO-TGI improves oxygenation and lung mechanics and does not adversely affect hemodynamics, CO2 elimi-nation, ICP, and CPP when used to ventilate TBI patients with severe ARDS RMs can cause hemody-namic complications and may have to be cancelled or aborted

Key messages

• The use of HFO in patients with TBI is limited because of hypercapnia that occurs commonly

Table 3 Shunt fraction, peripheral perfusion indices, and hemodynamics

Ventilatory strategy Shunt fraction ScvO 2 (%) Heart rate (beats/min) MAP (mm Hg)

HFO-TGI (4 hours) 0.31 ± 0.09* 74.0 ± 3.9 *,§ 92 ± 23 94 ± 13

HFO-TGI (8 hours) 0.29 ± 0.06* 74.6 ± 4.1 *,§ 92 ± 23 93 ± 14

HFO-TGI (12 hours) 0.29 ± 0.06* 75.0 ± 4.1 *,§ 92 ± 22 90 ± 15

Ventilatory strategy Cardiac Index (L/min/m2BSA) DO 2 Index

(ml/min/m 2 BSA)

Arterial blood lactate (mM) CVP (mm Hg)

HFO-TGI (4 hours) 4.7 ± 1.1 541 ± 119 § 1.82 ± 0.68 12 ± 3.0

HFO-TGI (8 hours) 4.8 ± 1.1 553 ± 114 *,§ 1.85 ± 0.68 12 ± 2.9

HFO-TGI (12 hours) 4.7 ± 1.2 551 ± 119 *,§ 1.82 ± 0.69 12 ± 2.8

Values are mean ± SD CMV, conventional mechanical ventilation; HFO, high-frequency oscillation; TGI, tracheal gas insufflation; pre-HFO-TGI CMV, corresponds to either the baseline CMV period of study day 1, or the 60-minute period that followed the 11-hour period of post-HFO-TGI CMV of the preceding study day (see also Figure 1 and corresponding legend); ScvO2, central venous O2 saturation; MAP, mean arterial pressure; BSA, body surface area; DO2, peripheral O2 delivery; CVP, central venous pressure.

* P < 0.01 versus pre-HFO-TGI CMV

§

P < 0.05 versus post-HFO-TGI CMV

during HFO, even at relatively low HFO frequencies

of about5 Hz Hypercapnia can have deleterious

effects on ICP and CPP

• The addition of TGI to HFO improves oxygenation

and enhances CO2elimination, thereby providing a

theoretically suitable lung-protective strategy for

patients with ARDS/TBI

• In this work, we showed that rescue sessions of

HFO-TGI administered to TBI patients with severe

ARDS result in improved gas exchange, higher

post-HFO-TGI respiratory compliance, and less-traumatic

CMV pressures, without adversely affecting ICP and/

or CPP

• Our findings support the design of randomized

controlled trials to evaluate the use of HFO-TGI in

patients with ARDS and TBI

Additional material

Additional file 1: Electronic Supplementary Material to

High-Frequency Oscillation and tracheal gas insufflation in patients with

severe acute respiratory distress syndrome and traumatic brain

injury: An interventional physiological study Details of methods and

data not shown in the main manuscript.

Abbreviations

ARDS: acute respiratory distress syndrome; CMV: conventional mechanical

ventilation; CPP: cerebral perfusion pressure; ECMO: extracorporeal

membrane oxygenation; E cw : chest wall elastance; E L : lung elastance; FiO 2 :

fractional inspired O2; HFO: high-frequency oscillation; HFPV: high-frequency

percussive ventilation; ICP: intracranial pressure; mP aw : mean airway pressure;

pECLA: pumpless extracorporeal lung assist; PEEP: positive end-expiratory

pressure; P pl : intrapleural pressure; RM: recruitment maneuver; TBI: traumatic

brain injury; TGI: tracheal gas insufflation; TIL: therapy intensity level; ΔP:

oscillatory pressure amplitude.

Competing interests

The authors declare that they have no competing interests.

Authors ’ contributions

CSV, SGZ, and SDM contributed to the conception and design of the study.

SDM and SMa collected the data CSV and SDM analyzed and interpreted

the data All authors contributed to the discussion of the results CSV and

SMa drafted the manuscript, and SGZ and SDM critically revised it All

authors read and approved the final manuscript for publication.

Acknowledgements

The authors thank Dr Stelios Kokkoris for his contribution in the collection

of clinical data This research was co-financed by the European Union

(European Social Fund, ESF) and Greek national funds through the

Operational Program “Education and Lifelong Learning” of the National

Strategic Reference Framework (NSRF)-Research Funding Program:

Heracleitus II, Investing in Knowledge Society through the European Social

Fund.

Received: 17 March 2013 Revised: 16 May 2013 Accepted: 11 July 2013

Published: 11 July 2013

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doi:10.1186/cc12815

Cite this article as: Vrettou et al.: High-frequency oscillation and tracheal

gas insufflation in patients with severe acute respiratory distress

syndrome and traumatic brain injury: an interventional physiological

study Critical Care 2013 17:R136.

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